Small-molecule "BRCA1-mimetics" are antagonists of estrogen receptor-?.

ABSTRACT: Resistance to conventional antiestrogens is a major cause of treatment failure and, ultimately, death in breast cancer.The objective of the study was to identify small-molecule estrogen receptor (ER)-? antagonists that work differently from tamoxifen and other selective estrogen receptor modulators.Based on in silico screening of a pharmacophore database using a computed model of the BRCA1-ER-? complex (with ER-? liganded to 17?-estradiol), we identified a candidate group of small-molecule compounds predicted to bind to a BRCA1-binding interface separate from the ligand-binding pocket and the coactivator binding site of ER-?. Among 40 candidate compounds, six inhibited estradiol-stimulated ER-? activity by at least 50% in breast carcinoma cells, with IC50 values ranging between 3 and 50 ?M. These ER-? inhibitory compounds were further studied by molecular and cell biological techniques.The compounds strongly inhibited ER-? activity at concentrations that yielded little or no nonspecific toxicity, but they produced only a modest inhibition of progesterone receptor activity. Importantly, the compounds blocked proliferation and inhibited ER-? activity about equally well in antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. Representative compounds disrupted the interaction of BRCA1 and ER-? in the cultured cells and blocked the interaction of ER-? with the estrogen response element. However, the compounds had no effect on the total cellular ER-? levels.These findings suggest that we have identified a new class of ER-? antagonists that work differently from conventional antiestrogens (eg, tamoxifen and fulvestrant).

SUBMITTER: Ma Y 

PROVIDER: S-EPMC4250363 | biostudies-other | 2014 Dec

REPOSITORIES: biostudies-other